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Comprehensive characterization of the Published Kinase Inhibitor Set
DOI:
10.1038/nbt.3374
PMID:
26501955
Authors:
Jonathan M
Elkins
(University of Oxford)
,
Vita
Fedele
(University of Oxford)
,
Marta
Szklarz
(University of Oxford)
,
Kamal R
Abdul Azeez
(University of Oxford)
,
Eidarus
Salah
(University of Oxford)
,
Jowita
Mikolajczyk
(Nanosyn, Inc)
,
Sergei
Romanov
(Nanosyn, Inc)
,
Nikolai
Sepetov
(Nanosyn, Inc)
,
Xi-Ping
Huang
(The University of North Carolina Chapel Hill School of Medicine)
,
Bryan L
Roth
(The University of North Carolina Chapel Hill School of Medicine)
,
Ayman
Al Haj Zen
(University of Oxford)
,
Denis
Fourches
(The University of North Carolina Chapel Hill School of Medicine)
,
Eugene
Muratov
(The University of North Carolina Chapel Hill School of Medicine)
,
Alex
Tropsha
(The University of North Carolina Chapel Hill School of Medicine)
,
Joel
Morris
(National Cancer Institute)
,
Beverly A
Teicher
(National Cancer Institute)
,
Mark
Kunkel
(National Cancer Institute)
,
David H
Drewry
(GlaxoSmithKline)
,
William J
Zuercher
(GlaxoSmithKline)
,
Stefan
Knapp
(Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Nature Biotechnology
State:
Published (Approved)
Published:
October 2015
Abstract: Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein–coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.
Journal Keywords: Chemical Tools; Screening; Target Validation; X-Ray Crystallography
Subject Areas:
Biology and Bio-materials,
Medicine,
Chemistry
Instruments:
I03-Macromolecular Crystallography
,
I04-1-Macromolecular Crystallography (fixed wavelength)
Added On:
23/11/2015 10:53
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Chemistry
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)